2. Definitions
• Antibiotic – Substance of biological origin like fungi and
Actinomycetes which inhibits the growth of other organisms
• Antimicrobial agent – Any compound - natural or synthetic or semi
synthetic that is active against microorganisms
• Chemotherapeutic agent – Synthetic chemical
• Bacteriostatic agents (Sulphonamides &Chloramphenicol) - inhibits
the growth of microorganisms
• Bactericidal agent – Kills microorganisms
• Therapeutic index - The ratio of the dose toxic to the host to the
effective therapeutic dose.
3. History of Antimicrobial Therapy
• 1909 Paul Ehrlich
• Differential staining of tissue, bacteria
• Search for magic bullet that would attack bacterial structures, not ours.
• Developed salvarsan, used against syphilis.
4. • 1929 Penicillin discovered by Alexander Fleming
• 1940 Florey and Chain mass produce penicillin for
war time use, becomes available to the public.
• 1935 Sulfa drugs discovered
• 1944 Streptomycin discovered by Waksman from
Streptomyces griseus
7. Historical distinctions
• Antibiotics: substances produced by organisms that
have inhibitory effects on other organisms.
• Penicillin, streptomycin
• Synthetic drugs: produced in a lab.
• Salvarsan, sulfa drugs
• Nowadays, most antimicrobials are semi-synthetic
• Distinction between “antibiotics” and “synthetic drugs” slowly
being abandoned.
8. Where do antibiotics come from?
• Several species of fungi including Penicillium and
Cephalosporium
• E.g. penicillin, cephalosporin
• Species of actinomycetes, Gram positive filamentous bacteria
• Many from species of Streptomyces
• Also from Bacillus, Gram positive spore formers
• A few from myxobacteria, Gram negative bacteria
• New sources explored: plants, herps, fish
11. VI. Antibacterial Agents
A. Inhibitors of cell wall synthesis
1. Penicillins
2. Cephalosporins
3. Other antibacterial agents that act on cell walls
B. Disrupters of cell membranes
1. Polymyxins
2. Tyrocidins
C. Inhibitors of protein synthesis
1. Aminoglycosides
2. Tetracyclines
3. Chloramphenicol
4. Other antibacterial agents that affect protein synthesis
a. Macrolides
b. Lincosamides
D. Inhibitors of nucleic acid synthesis
1. Rifampin
2. Quinolones
E. Antimetabolites and other antibacterial agents
1. Sulfonamides
2. Isoniazid
3. Ethambutol
4. Nitrofurans
12.
13. Antibiotic Mechanisms of Action
Transcription
Translation
Translation
Alteration of
Cell Membrane
Polymyxins
Bacitracin
Neomycin
14. 1-Inhibition of cell wall synthesis
• beta-lactam containing antibiotics inhibit
transpeptidase; bacteria cannot synthesize
reinforced cell wall and they lyse when they try to
grow
• Vancomycin and cyclo-Ser inhibit specific binding
of Ala’s in crossbridges to transpeptidase in many
gram+ bacteria
• Bacitracin inhibits secretion of NAG and NAM
subunits
• All of these only kill growing bacteria
15. Inhibition of cell wall synthesis
Betalactum antibiotics
• Penicillin
• Cephalosporins
• Other betalactum
antibiotics like
Carbapenum
(Imipenum, Meropenum)
Monobactams-aztreonam
Other inhibitors
• Isoniazid and
Ethionamide– block
mycolic acid synthesis
• Ethambutol – interferes
synthesis of
arabinogalactan of cell wall
• Cycloserine – inhibits D-
alanine synthetase and
alanine racemase
important for cell wall
synthesis
19. 1. Penicillins
• Penicillins contain a b-lactam ring which inhibits the
formation of peptidoglycan crosslinks in bacterial cell
walls (especially in Gram-possitive organisms)
• Penicillins are bactericidal but can act only on dividing
cells
• They are not toxic to animal cells which have no cell wall
20.
21. Synthesis of Penicillin
b-Lactams produced by fungi, some ascomycetes,
and several actinomycete bacteria
b-Lactams are synthesized from amino acids valine
and cysteine
23. Penicillins
Resistance
• This is the result of production of b-lactamase enzyme in the
bacteria which destroys the b-lactam ring
• It occurs in e.g. Staphylococcus aureus, Haemophilus influenzae and
Neisseria gonorrhoea
24. Penicillins
Examples
• There are now a wide variety of penicillins, which may be acid labile
(i.e. broken down by the stomach acid and so inactive when given
orally) or acid stable, or may be narrow or broad spectrum in action
• Benzylpenicillin (Penicillin G) is acid labile and b-lactamase sensitive
and is given only parenterally
• It is the most potent penicillin but has a relatively narrow spectrum
covering Strepptococcus pyogenes, S. pneumoniae, Neisseria
meningitis or N. gonorrhoeae, treponemes, Listeria, Actinomycetes,
Clostridia
25. Penicillins
Examples
• Phenoxymethylpenicillin (Penicillin V) is acid stable and is given orally
for minor infections
• it is otherwise similar to benzylpenicillin
• Ampicillin is less active than benzylpenicillin against Gram-possitive
bacteria but has a wider spectrum including (in addition in those
above) Strept. faecalis, Haemophilus influenza, and some E. coli,
Klebsiella and Proteus strains
• It is acid stable, is given orally or parenterally, but is b-laclamase
sensitive
26. Penicillins
Examples
• Amoxycillin is similar but better absorbed orally
• It is sometimes combined with clavulanic acid, which is a b-lactam
with little antibacterial effect but which binds strongly to b-lactamase
and blocks the action of b-lactamase in this way
• It extends the spectrum of amoxycillin
27. 2. Cephalosporins
• They also owe their activity to b-lactam ring and
are bactericidal.
• Produced from a fungus Cephalosporium
acremonium.
• Good alternatives to penicillins when a broad -
spectrum drug is required
• should not be used as first choice unless the
organism is known to be sensitive
28. Cephalosporins
• BACTERICIDAL- modify cell wall synthesis
• Interfere at the final step of peptidoglycan
synthesis ( Transpeptidation)
• CLASSIFICATION- first generation are early
compounds
• Second generation- resistant to β-lactamases
• Third generation- resistant to β-lactamases &
increased spectrum of activity
• Fourth generation- increased spectrum of activity
29. Cephalosporins
• FIRST GENERATION- eg cefadroxil, cefalexin, Cefadrine - most active vs
gram +ve cocci. An alternative to penicillins for staph and strep infections;
useful in UTIs
• SECOND GENERATION- eg cefaclor and cefuroxime. Active vs
enerobacteriaceae eg E. coli, Klebsiella spp,proteus spp. May be active vs H
influenzae and N meningtidis
• THIRD GENERATION- eg cefixime and other I.V.s
cefotaxime,ceftriaxone,ceftazidine. Very broad spectrum of activity inc
gram -ve rods, less activity vs gram +ve organisms.
• FOURTH GENERATION- cefpirome better vs gram +ve than 3rd generation.
Also better vs gram -ve esp enterobacteriaceae & pseudomonas
aerugenosa. I.V. route only
• FIFTH GENERATION- Ceftaroline, Ceftabiprole- four generation spectrum
plus Pseudomonas and MRSA
30.
31. 3. Aminoglycosides
a) Mode of action - Irreversibly bind to the 30S ribosome
and freeze the 30S initiation complex, slow down protein
synthesis that has already initiated and induce misreading of
the mRNA.
b) Spectrum of Activity - Many gram-negative and some
gram-positive bacteria; Not useful for anaerobic or
intracellular bacteria
c)Resistance – Common
d) Synergy - Synergize with β-lactam antibiotics which inhibit
cell wall synthesis and thereby increase the permeability of
the aminoglycosides
32. 4. Tetracycline
a) Mode of action - Reversibly bind to the 30S ribosome and inhibit
binding of aminoacyl-t-RNA to the acceptor site on the 70S ribosome.
b)Spectrum of activity - Broad spectrum; Useful against intracellular
bacteria
c) Resistance - Common
d) Adverse effects - Destruction of normal intestinal flora resulting in
increased secondary infections; staining and impairment of the
structure of bone and teeth
33. 5. Other Antibiotics
Macrolides (bacteriostatic)
1)Erythromycin
a) Mode of action - The macrolides inhibit translocation.
b) Spectrum of activity - Gram-positive bacteria, Mycoplasma,
Legionella
c) Resistance – Common
2)Azithromycin – S.pyogenes and S.pneumoniae
3)Clarithramycin – H.pylori gastritis & M.intracellulare
34. Other Antibiotics
Chloramphenicol, lincomycin, clindamycin (bacteriostatic)
a) Mode of action – They bind to the 50S ribosome and inhibit
peptidyl transferase activity.
b) Spectrum of activity
1) Chloramphenicol - Broad range
2) Lincomycin -and clindamycin - Restricted range
c) Resistance - Common
d) Adverse effects - Chloramphenicol is toxic (bone marrow
suppression) but it is used in the treatment of bacterial meningitis.
35. Other Antibiotics- Vancomycin
• This interferes with bacterial cell wall formation and is not absorbed
after oral administration and must be given parenterally.
• It is excreted by the kidney.
• It is used i.v. to treat serious or resistant Staph. aureus infections and
for prophylaxis of endocarditis in penicillin-allergic people.
36. Other Antibiotics- Quinolones (bactericidal)
nalidixic acid, ciprofloxacin, ofloxacin, norfloxacin, levofloxacin, lomefloxacin, sparfloxacin
• Mode of action - These antimicrobials bind to the A
subunit of DNA gyrase (topoisomerase) and prevent
supercoiling of DNA, thereby inhibiting DNA synthesis.
• Spectrum of activity - Gram-positive cocci and urinary tract
infections
• Resistance - Common for nalidixic acid; developing for
ciprofloxacin
38. Quinolones
Examples and clinical pharmacokinetics
• Nalidixic acid, the first quinolone, is used as a urinary antiseptic and
for lower urinary tract infections, as it has no systemic antibacterial
effect.
• Ciprofloxacin is a fluoroquinolone with a broad spectrum against
Gram-negative bacilli and Pseudomonas,
• It can be given orally or i.v. to treat a wide range of infections,
including respiratory and urinary tract infections as well as more
serious infections, such Salmonella.
• Activity against anaerobic organism is poor and it should not be first
choice for respiratory tract infections.
39. Other Antibiotics- Metronidazole
• Metronidazole binds to DNA and blocks replication.
• Metronidazole is active against anaerobic organisms (e.g. Bacteroides,
Clostridia), which are encountered particularly in abdominal surgery.
• It is also used against Trichomonas, Giardia and Entamoeba
infections.
• Increasingly, it is used as part of treatment of Helicobacter pyloris
infestion of the stomach and duodenum associated with peptic ulcer
disease.
• It is used also to treat a variety of dental infections, particularly
dental abscess
40. Other Antibiotics- Nitrofurantoin
• This is used as a urinary antiseptic and to treat
Gram-negative infections in the lower urinary
tract. It is also used against Trypanosoma
infections.
• It is taken orally and is well absorbed and is
excreted unchanged in the urine.
41. Other Antibiotics- Sulfonamides and
trimethoprim
• Sulfonamides are rarely used alone today.
• Trimethoprim is not chemically related but is considered here
because their modes of action are complementary.
42. Sulfonamides, Sulfones (bacteriostatic)
• Mode of action - These antimicrobials are analogues of para-
aminobenzoic acid and competitively inhibit formation of
dihydropteroic acid.
• Spectrum of activity - Broad range activity against gram-positive
and gram-negative bacteria; used primarily in urinary tract and
Nocardia infections.
• Resistance - Common
• Combination therapy - The sulfonamides are used in
combination with trimethoprim; this combination blocks two
distinct steps in folic acid metabolism and prevents the
emergence of resistant strains.
43. Trimethoprim, Methotrexate,
(bacteriostatic)
• Mode of action - These antimicrobials binds to
dihydrofolate reductase and inhibit formation of
tetrahydrofolic acid.
• Spectrum of activity - Broad range activity against gram-
positive and gram-negative bacteria; used primarily in
urinary tract and Nocardia infections.
• Resistance - Common
• Combination therapy - These antimicrobials are used in
combination with the sulfonamides; this combination
blocks two distinct steps in folic acid metabolism and
prevents the emergence of resistant strains.
45. Sulfonamides and trimethoprim
Mode of action
• Folate is metabolized by enzyme dihydrofolate reductase to the active
tetrahydrofolic acid.
• Trimethoprim inhibits this enzyme in bacteria and to a lesser degree
in animal s, as the animal enzyme is far less sensitive than that in
bacteria.
48. 48
DEFINITION
• is the ability of the parasite to survive and/or multiply despite the administration
and absorption of a drug given in doses that is equal to or higher than those
usually recommended
49. 49
Mechanism
• produces enzymes that destroy the active drug
eg.,Staphylococci’s beta lactamases destroying Penicillin
• Alteration in permeability
eg., Tetracycline accumulates in susceptible bacteria not in resistant
bacteria
• Developing altered structural target for the drug
eg., erythromycin resistant bug having an altered receptor on 50s
subunit of the ribosome
• Developing an altered metabolic pathway
eg.,sulfonamide resistant organism utilizing preformed folic acid
• Developing an altered enzyme that are much less affected
by the drug
50. 50
Origin
• NON GENETIC ORIGIN:
-non multiplying organism resistant to drugs
-cell wall deficient strains are resistant to cell wall inhibitors
-intracellular organisms resistance to aminoglycosides
• GENETIC ORIGIN:
-chromosomal by means of mutation
-Extra chromosomal by means of plasmids
51.
52. 52
Cross resistance
• Micro organisms resistant to a certain drugs may also be resistant to other drugs
that share a mechanism of action
eg., tetracyclines
53. 53
Genetic basis of resistance
• CHROMOSOMAL :
-spontaneous mutation in locus controlling susceptibility to the drug
-presence of drug favour growth of mutant
-causes a change in structural receptor of the drug
-eg., loss of PBP resulting resistance to beta lactum drugs etc.,
54. 54
• EXTRA CHROMOSOMAL:
-R Plasmid associated
- carry genes for one or multiple drug resistance
-often forms enzymes capable of destroying drugs- beta lactamase
-codes for enzymes that Acetylate, adenylylate, or phosporylate
aminoglycosides
-enzymes determining active transport of Tetracycline across cell wall
56. 56
Tranposons
• Movable DNA elements carrying genes
• Has ability to ‘hop’ from plasmid to plasmid and between
plasmid to chromosomes- JUMPING GENE
• May carry single or multiple resistance
• Can enter and remain stable in different species, hence spreads
R markers throughout the bacterial kingdom
57. 57
• Generally chromosomal resistance is SINGLE, LOW LEVEL
usually NON ENZYMATIC
• Plasmid or Transposon resistance are HIGH LEVEL,
MULTIPLE and ENZYMATIC
58. 58
Methicillin Resistant Staphylococcus aureus
• MRSA/ORSA
• Independent of beta lactamase production
• Due to mecA gene presence on the chromosome
• Causes lack or inaccessibility of certain PBPs in the
organism
• Shows resistance to other as well
• Mainly colonized groin, axilla, perineum esp., HCW
• Susceptible to glycopeptide antibiotics like vancomycin,
teicoplanin etc.,
59. 59
Multi Drug Resistant Tuberculosis
• MDR-TB
• Primary drug resistance in M.tb occurs in 10% of isolates
commonly to H and S
• H and R are the primary drugs in most of the regimens
• Resistance to H and R is considered as MDR-TB
• Resistance to other drugs also seen
• Highest rates are seen in Nepal, India, New York etc.,
• Due to alterations in genes eg., cat gene for H etc.,
• Poor compliance is responsible
• Significant world wide problem
60. 60
Extended Spectrum ß Lactamase
• Kind of ß Lantanas produced by GNB confers resistance to
III generation cephalosporins and aztreonam
• All sensitive to carbapenam drugs
• Either plasmid or chromosomal mediated
61. Antifungal Agents
A. Imidazoles and triazoles
B. Polyenes
1. Amphotericin B
2. Nystatin
C. Griseofulvin
D. Other antifungal agents
1. Flucytosine
2. Tolnaftate
3. Terbinafine
Antiviral Agents
A. Purine and pyrimidine analogues
1. Idoxuridine and trifluridine
2. Vidarabine
3. Ribavirin
4. Acyclovir
5. Ganciclovir
6. Zidovudine
B. Amantadine
C. Treatment of AIDS
